WO1995011039A1 - PHARMACEUTICAL COMPOSITION CONTAINING CYCLOSPORINE A AND α-TOCOPHEROL - Google Patents
PHARMACEUTICAL COMPOSITION CONTAINING CYCLOSPORINE A AND α-TOCOPHEROL Download PDFInfo
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- WO1995011039A1 WO1995011039A1 PCT/EP1994/003274 EP9403274W WO9511039A1 WO 1995011039 A1 WO1995011039 A1 WO 1995011039A1 EP 9403274 W EP9403274 W EP 9403274W WO 9511039 A1 WO9511039 A1 WO 9511039A1
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- tocopherol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Definitions
- the invention relates to pharmaceutical Caribbeansetzun ⁇ gen holding E concentrates ent an effective amount Cycl 'osporin A in combination with Vitamin E.
- Cyclosporin A is a cyclic, water-insoluble, non-polar undecapeptide.
- the compound is a potent immunosuppressant obtained from fungal cultures (Cane et al., Transplant TROC. 13: 349-358 (1981); Ferguson et al., Surgery 92: 175-182 (1982)).
- the drug is used to prevent rejection of transplanted allogeneic organs (Bennett & Norman, Arzn. Rev. Med. 37, 215-224 (1986); Van Basen, Surg. Clin. North Am. 66, 435-449 (1986)) .
- Its immunosuppressive effect is based on a selective inhibition of cell function, which survive from Z. B.
- Cyclosporin is a lipophilic molecule with a molecular weight of 1202 daltons. Because of the poor water solubility and the high lipophilicity of cyclosporin A, its pharmaceutical compositions with conventional solid or liquid pharmaceutical carriers often have disadvantages. Thus, the cyclosporins from such compositions are not satisfactorily absorbed (Cavanak & Sucker, Formulation of Dosage Forms, Prog. Allergy 38, 65-72 (1986)), or the compositions are not well tolerated, or they are in the Storage not sufficiently stable, for example against the crystallization of the cyclosporin. Often the dissolved concentration is low in relation to the dose of up to 1 g daily, e.g. B.
- DE-B-2 907 460 describes a solution of cyclosporin in vegetable oil such as olive oil or corn oil, ethanol and an emulsifier from a nonionic ester of a triglyceride with a polyalkylene glycol.
- examples of the compositions specified by this patent are drinking solution, drinking emulsion, injection solution and solution in capsules.
- the above composition is preferably administered intramuscularly, or subcutaneously, or in particular orally.
- Cy ⁇ closporin A applied with the above dosage forms, is characterized by good bioavailability. Binds after absorption the substance rapidly on plasma proteins and has a terminal half-life of 24 hours. A high percentage is metabolized in the liver, with biliary excretion being the main route of elimination (Beverige, Cyclosporin A; in: Proceedings of International Symposium, Cambridge, Ed. White, pages 35-44 (1982)).
- kidney toxicity also occurs in about 80% of kidney transplant patients (Kahan, Dial. Transplant. 12: 620-30 (1983)), specifically because of this substance-inherent side effect which is used to protect the transplant from rejection.
- cyclosporin treatments in various autoimmune diseases include nephrotoxicity, hypertension, hyperkalemia, hyperuricoemia, hepatotoxicity, anemia, hypertrichiosis, gingival hyperplasia, gastrointestinal side effects, tremor and paresthesia (Von Graffenriedine et al. Scheme Disporler, ed , Springer Verlag, Berlin, pages 59-73 (1985)).
- nephrotoxicity The acute nephrotoxicity induced by cyclosporin is dose-dependent and correlates with the cyclosporin blood levels. It is reversible after dose reduction or after termination of cyclosporine therapy (Chapman et al., Lancet I: 128 (1985)).
- Acute cyclosporin ephrotoxicity is morphologically associated with tubular lesions which are characterized by inclusion bodies, isometric vacuolization and microcalcification (Miihatsch et al., Transplant. Proc. 15: 2821 (1983)). This leads to a decrease in the glomerular filtration rate, as can be seen from the rapid increase in serum creatinine in cyclosporin-treated patients.
- One reason could be the disturbance of the microcirculation due to interaction of cyclosporin with the local prostacyclin synthesis (Neild et al.; in: Cyclosporine, editor Kahan, Gruen & Stratton, Orlando, Flo ⁇ rida, page 182 (1984)).
- Thromboxan is a prostanoid and therefore a metabolite of arachidonic acid from the cyclooxygenase cycle.
- the other prostanoids are prostaglandins and prostacyclins.
- Prostanoids are very effective mediators that arise during immunologically generated inflammatory processes. They can fundamentally change renal hemodynamics (Morley; in: Lymphokines, publisher Pic, Academic Press, New York, 4: 377-391 (1981)).
- EP-A-20 305 400 describes the connections between impaired prostanoid synthesis and nephrotoxicity. Thereafter, the administration of cyclosporin is accompanied by an increased synthesis of thromboxane B2, a mediator of inflammation. Accordingly, cyclosporin should also promote the formation of prostaglandins of the E series, also inflammation mediators. The rejection of human kidney transplants has been associated with a rapid increase in renally eliminated thromboxane B2.
- EP-A-0 305 400 also describes the use of w3-unsaturated fatty acids in combination with cyclosporin A to inhibit prostaglandin or thromboxane formation.
- a disadvantage of long-term w3 fatty acid administration is the development of a vitamin E deficiency.
- Deficiency states are e.g. B. hemolysis and a shortened lifespan of the erythrocytes.
- vitamin E deficiency leads to degenerative muscle changes in the muscles, creatinuria, increased hemolysis of the erythrocytes and to influence certain hormones and enzymes as well as the protein and arachidonic acid metabolism (Machlin, Vitamin E.; in: Machlin, Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects, pages 99-145, Marcel Dekker, New York, 1984).
- EP-A-0 305 400 only describes a concentration with 12.5 mg cyclosporin A per gram of fish oil. With a usual daily dose of more than 300 mg cyclosporin A, this means a total intake of about 24 grams of the preparation, with 1 g cyclosporin A of 80 g preparation. This is an oil level that is unacceptably high for patients. Encapsulated in soft gelatin capsules, for example, would lead to the daily intake of 24 capsules containing 300 mg cyclosporin A. Parenteral application by infusion would be, with an optimistic calculation, 10 percent.
- oil-containing infusion emulsion means an amount of approximately 240 ml of emulsion with 300 mg of cyclosporin A, a volume which can only be infused over a longer period of time. Both aspects stand in the way of a chronic application, as is necessary in transplant patients.
- the formulations according to DE-B-2 907 460 are distinguished by a very high solubility for cyclosporin A, but have the disadvantage that they only comprise vegetable oils which do not contain any substances which inhibit prostaglandin or thromboxane synthesis. This means that the nephro-toxicity of cyclosporin A is not inhibited by these preparations.
- the commercially available parenteral solution of cyclosporin A (Sandimmun R , Sandoz) contains in 1 ml solution 50 mg cyclosporin A, 32.9% ethanol and 650 mg cremeopher EL, an ethoxylated, hydrogenated castor oil.
- Cremeopher EL is nephrotoxically similar to cyclosporin A itself (Thiel et al., Clin. Nephrol. 25 (Suppl. 1), 540-542 (1986); Finn et al., Renal Failure 11, 3-15 (1989)).
- Cremeopher EL leads to a clear renal vasoconstriction with reduced renal blood flow and tubular dysfunction in the isolated, perfused rat kidney (Besarab et al., Transplantation 44, 195-201 (1987); Luke et al., Transplantation 43, 795-799 (1987)).
- Cremeopher EL causes anaphylactic reactions up to shock (Chapuis et al., Engl. J. Med. 312, 1259 (1985), Leunissen et al., Lancet 1, 637 (1986); Magalini et al. , Transplantation 42, 443-444 (1986)). Cremop er EL was considered to be the cause of the anaphylactoid reaction since it leads to histamine liberation (Ennis et al., Agents Action 12, 64-80 (1982)). In some therapy cases with the iv solution, the allergic reaction was observed when it was first used in humans (Friedman et al., Am J.
- cyclosporin A The beneficial immunosuppressive properties of cyclosporin A are used in the treatment of psoriasis.
- cyclosporin A due to its high molecular weight and its very high lipophilicity, cyclosporin A is unable to penetrate intact skin, especially the stratum corneum. For this reason, severe psoriasis cases are treated with oral and parenteral cyclospore administration.
- the disadvantage of this application is the systemic side effects on the circulation (hypertension) and kidney function.
- Topical preparations for the treatment of psoriasis which would reduce the systemic side effects, require absorption promoters such as.
- B. Propylene glycol and Azone (Duncan et al., British Journal of Dermatology 123: 631-640 (1990)).
- This pharmaceutical preparation can be characterized by ⁇ -tocopherol succinate, ⁇ -tocopherol acetate or D- ⁇ -tocopherol polyethylene glycol 1000 succinate as ⁇ -tocopherol derivative.
- the pharmaceutical preparation can furthermore be characterized by a content of ⁇ -tocopherol in the form of an ⁇ -tocopherol concentrate in vegetable oil.
- the pharmaceutical preparation can be obtained by mixing cyclosporin A with an ⁇ -tocopherol concentrate in vegetable oil.
- the pharmaceutical preparation can further be characterized by a content of ⁇ -tocopherol or one of its derivatives of up to 900% based on cyclosporin A.
- the pharmaceutical preparation can also be characterized by a content of cyclosporin A> 10% based on the composition.
- the pharmaceutical preparation can also be characterized by its ethanol or isopropanol content as processing aid, in particular in amounts of up to 20%.
- the pharmaceutical preparation can furthermore be characterized by a content of an emulsifier.
- the pharmaceutical preparation can also be characterized by a thickener content.
- the pharmaceutical preparation can be provided in the form of an injection concentrate for parenterals with customary physiologically compatible auxiliaries.
- ⁇ -tocopherol and its chemical derivatives such as ⁇ -tocopherol succinate and D- ⁇ -trocopherol polyethylene glycol 1000 succinate and ⁇ -tocopherol acetate, but especially highly concentrated concentrates of D- ⁇ -Tocopherol in vegetable oils, have an excellent solvent capacity for cyclosporin A, at the same time inhibit the synthesis of prostanoids such as prostaglandins and thromboxanes, which can be used to reduce the nephrotoxicity and to subside inflammatory reactions in the skin and
- vitamin E increases skin moisture and acts as an occlusion agent. All of these properties described are beneficial in treating psoriasis.
- Cyclosporin A now completely unexpectedly dissolves in such a high concentration> 10% in vitamin E preparations as vitamin E concentrates (Copherol F 1300), so that the combination as a solution can be used therapeutically in both soft gelatin capsules and in topical formulations is.
- the formulations can contain small amounts of alcohol such as ethanol or isopropanol in amounts of up to 20% of the total formulation and also to promote the wetting of physiologically compatible surface-active substances, that is to say emulsifiers.
- Both orally and topically compatible emulsifiers are, for example, phospholipids such as lecithins, lysolecithins, ethoxylation products of fatty acids and fats, alkali soaps, sucrose esters and others, without being limited thereto.
- the formulations can contain thickeners, such as colloidal silica or polyacrylic acid or polyacrylic acid derivatives or cellulose derivatives, and also antioxidants and flavor aids.
- Example 1 Composition for a soft gelatin capsule
- Example 2 Composition for a soft gelatin capsule
- Example 3 Composition for a soft gelatin capsule
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Abstract
Description
PHARMAZEUTISCHE ZUSAMMENSETZUNG MIT CYCLOSPORIN A UND ALPHA-TOCOPHEROL PHARMACEUTICAL COMPOSITION WITH CYCLOSPORIN A AND ALPHA-TOCOPHEROL
1. Gebiet der Erfindung1. Field of the Invention
Die Erfindung bezieht sich auf pharmazeutische Zusammensetzun¬ gen, die eine wirksame Menge Cycl'osporin A in Kombination mit Vitamin E., Vitamin E-Derivaten oder Vitamin E-Konzentraten ent¬ halten, bei denen natürliches Vitamin E neben Pflanzenölbestand- teilen vorliegt.The invention relates to pharmaceutical Zusammensetzun¬ gen holding E concentrates ent an effective amount Cycl 'osporin A in combination with Vitamin E. Vitamin E derivatives or Vitamin where natural vitamin E is present in addition to sharing Pflanzenölbestand-.
2. Stand der Technik2. State of the art
Cyclosporin A ist ein zyklisches, wasserunlösliches, unpolares Undekapeptid. Die Verbindung ist ein gut wirksames Immunsuppres- sivum, gewonnen aus Pilzkulturen (Cane et al . , Transplant TROC. 13: 349-358 (1981); Ferguson et al . , Surgery 92: 175-182 (1982)). Der Arzneistoff wird zur Vorbeugung der Abstoßung transplantierter allogener Organe eingesetzt (Bennett & Norman, Arzn. Rev. Med. 37, 215-224 (1986); Van Basen, Surg. Clin. North Am. 66, 435-449 (1986)). Seine i munsuppressive Wirkung beruht auf einer selektiven Hemmung der Zellfunktion, die ein überleben von z. B. Herztransplantaten ohne Myelozytensuppression erlaubt (Myers et al , New England Journal of Medicine 311: 699 (1984)). Zusätzlich zur Verwendung bei Transplantationen haben neuere klinische Prüfungen gezeigt, daß Cyclosporin A bei der Behand¬ lung einer großen Anzahl von Autoimmunerkrankungen wirksam ist. Beispielsweise wurden klinische Prüfungen zur Behandlung von Polymyositis, systemischem Lupus Erythematodes, Rheumatischer Arthritis oder sogar von jugendlichem insulinabhängigen Diabetes durchgeführt (siehe die entsprechenden Kapitel in: Cyclosporine in Autoimmune Diseases, Herausgeber Schindler, Springer Verlag, Berlin 1985).Cyclosporin A is a cyclic, water-insoluble, non-polar undecapeptide. The compound is a potent immunosuppressant obtained from fungal cultures (Cane et al., Transplant TROC. 13: 349-358 (1981); Ferguson et al., Surgery 92: 175-182 (1982)). The drug is used to prevent rejection of transplanted allogeneic organs (Bennett & Norman, Arzn. Rev. Med. 37, 215-224 (1986); Van Basen, Surg. Clin. North Am. 66, 435-449 (1986)) . Its immunosuppressive effect is based on a selective inhibition of cell function, which survive from Z. B. Heart transplants allowed without myelocyte suppression (Myers et al, New England Journal of Medicine 311: 699 (1984)). In addition to the use in transplants, recent clinical tests have shown that cyclosporin A is effective in the treatment of a large number of autoimmune diseases. For example, clinical trials for the treatment of polymyositis, systemic lupus erythematosus, rheumatoid arthritis or even juvenile insulin-dependent diabetes were carried out (see the corresponding chapters in: Cyclosporins in Autoimmune Diseases, publisher Schindler, Springer Verlag, Berlin 1985).
Cyclosporin ist ein lipophiles Molekül mit einem Molekularge¬ wicht von 1202 Dalton. Aufgrund der schlechten Wasserlöslichkeit und der hohen Lipophilie des Cyclosporin A besitzen dessen pharmazeutische Zusammensetzungen mit üblichen festen oder flüs¬ sigen pharmazeutischen Trägerstoffen oft Nachteile. So werden die Cyclosporine aus solchen Zusammensetzungen nicht zufrieden¬ stellend resorbiert (Cavanak & Sucker, Formulation of Dosage Forms, Prog. Allergy 38, 65-72 (1986)), oder die Zusammenset¬ zungen werden nicht gut vertragen, oder sie sind bei der Lage¬ rung nicht genügend stabil, beispielsweise gegen die Aus- kristallisation des Cyclosporins. Oft ist die gelöste Konzen¬ tration in Relation zur Dosis von bis zu 1 g täglich niedrig, z. B. nur 3 % , was die Einnahme von 30 g Lösung bedeutet. Eine hö¬ here Löslichkeit wird in DE-B-2 907 460 angeführt, worin eine Lösung von Cyclosporin in Pflanzenöl wie Olivenöl oder Maisöl, Ethanol und einem Emulgator aus einem nichtionischen Ester eines Triglyzerids mit einem Polyalkylenglycol beschrieben wird. Bei¬ spiele der von diesem Patent bevorzugt angegebenen Zusammenset¬ zungen sind Trinklösung, Trinkemulsion, Injektionslösung und in Kapseln befindliche Lösung.Cyclosporin is a lipophilic molecule with a molecular weight of 1202 daltons. Because of the poor water solubility and the high lipophilicity of cyclosporin A, its pharmaceutical compositions with conventional solid or liquid pharmaceutical carriers often have disadvantages. Thus, the cyclosporins from such compositions are not satisfactorily absorbed (Cavanak & Sucker, Formulation of Dosage Forms, Prog. Allergy 38, 65-72 (1986)), or the compositions are not well tolerated, or they are in the Storage not sufficiently stable, for example against the crystallization of the cyclosporin. Often the dissolved concentration is low in relation to the dose of up to 1 g daily, e.g. B. only 3%, which means taking 30 g of solution. A higher solubility is given in DE-B-2 907 460, which describes a solution of cyclosporin in vegetable oil such as olive oil or corn oil, ethanol and an emulsifier from a nonionic ester of a triglyceride with a polyalkylene glycol. Examples of the compositions specified by this patent are drinking solution, drinking emulsion, injection solution and solution in capsules.
Die Verabreichung der obigen Zusammensetzung erfolgt vorzugs¬ weise intramuskulär, oder subkutan, oder insbesondere oral. Cy¬ closporin A, appliziert mit obigen Arzneiformen, zeichnet sich durch eine gute Bioverfügbarkeit aus. Nach der Resorption bindet die Substanz schnell an Plasmaproteine und hat eine terminale Halbwertszeit von 24 Stunden. Es wird zu einem hohen Prozentsatz in der Leber metabol isiert, wobei die biliäre Exkretion die Haupteliminationsroute ist (Beverige, Cyclosporin A; in: Proceedings of International Symposium, Cambridge, Herausgeber White, Seiten 35-44 (1982)).The above composition is preferably administered intramuscularly, or subcutaneously, or in particular orally. Cy¬ closporin A, applied with the above dosage forms, is characterized by good bioavailability. Binds after absorption the substance rapidly on plasma proteins and has a terminal half-life of 24 hours. A high percentage is metabolized in the liver, with biliary excretion being the main route of elimination (Beverige, Cyclosporin A; in: Proceedings of International Symposium, Cambridge, Ed. White, pages 35-44 (1982)).
Trotz des großen Wertes als Immunsuppressivum ist die klinische Verwendung von Cyclosporin durch die Hauptnebenwirkung bei der chronischen Anwendung limitiert, die in der Nephrotoxizität des Wirkstoffes selber besteht (Van Buren, Surg. Clin. North Am. 66, 435-449 (1986)). Auch in etwa 80 % der Nierentransplantations¬ patienten tritt Nierentoxizität auf (Kahan, Dial. Transplant. 12: 620-30 (1983)), und zwar durch diese substanzimmanente Ne¬ benwirkung, die zum Schutz des Transplantates vor der Abstoßung angewendet wird.Despite its great value as an immunosuppressant, the clinical use of cyclosporin is limited by the main side effect in chronic use, which is the nephrotoxicity of the active substance itself (Van Buren, Surg. Clin. North Am. 66, 435-449 (1986)). Kidney toxicity also occurs in about 80% of kidney transplant patients (Kahan, Dial. Transplant. 12: 620-30 (1983)), specifically because of this substance-inherent side effect which is used to protect the transplant from rejection.
Häufige Nebeneffekte von Cyclosporinbehandlungen bei verschie¬ denen Autoimmunerkrankungen schließen der Nephrotoxizität, die Hypertension, Hyperkaliä ie, Hyperurikoämie, Hepatotoxizität, Anämie, Hypertrichiose, Gingivalhyperplasie, gastrointestinale Nebenwirkungen, Tremor und Paresthesien ein (Von Graffenried et al . , Cyclosporine in Autoimmune Diseases, Herausgeber Schindler, Springer Verlag, Berlin, Seiten 59-73 (1985)). Von den hier zi¬ tierten Nebenwirkungen ist die häufigste die Nephrotoxizität. Die akute, durch Cyclosporin induzierte Nephrotoxizität ist do¬ sisabhängig und korreliert mit den Cyclosporinblutspiegeln. Sie ist reversibel nach Dosisreduktion oder nach Beendigung der Cy- closporintherapie (Chapman et al . , Lancet I: 128 (1985)).Frequent side effects of cyclosporin treatments in various autoimmune diseases include nephrotoxicity, hypertension, hyperkalemia, hyperuricoemia, hepatotoxicity, anemia, hypertrichiosis, gingival hyperplasia, gastrointestinal side effects, tremor and paresthesia (Von Graffenriedine et al. Scheme Disporler, ed , Springer Verlag, Berlin, pages 59-73 (1985)). Of the side effects cited here, the most common is nephrotoxicity. The acute nephrotoxicity induced by cyclosporin is dose-dependent and correlates with the cyclosporin blood levels. It is reversible after dose reduction or after termination of cyclosporine therapy (Chapman et al., Lancet I: 128 (1985)).
Akute Cyclosporinnephrotoxizität geht morphologisch einher mit tubulären Läsionen, die durch Einschlußkörperchen, isometrische Vakuolisierung und Mikrocalzifizierung gekennzeichnet sind (Mi- hatsch et al . , Transplant. Proc. 15: 2821 (1983)). Dieses führt zu einer Abnahme der glomerulären Filtrationsrate, wie anhand des schnellen Anstiegs von Seru kreatinin in cyclosporinbehan- delten Patienten erkannt werden kann. Ein Grund dafür könnte die Störung der Mikrozirkulation durch Interaktion von Cyclospo¬ rin mit der lokalen Prostacyclinsynthese sein (Neild et al . ; in: Cyclosporine, Herausgeber Kahan, Gruen & Stratton, Orlando, Flo¬ rida, Seite 182 (1984)).Acute cyclosporin ephrotoxicity is morphologically associated with tubular lesions which are characterized by inclusion bodies, isometric vacuolization and microcalcification (Miihatsch et al., Transplant. Proc. 15: 2821 (1983)). This leads to a decrease in the glomerular filtration rate, as can be seen from the rapid increase in serum creatinine in cyclosporin-treated patients. One reason could be the disturbance of the microcirculation due to interaction of cyclosporin with the local prostacyclin synthesis (Neild et al.; in: Cyclosporine, editor Kahan, Gruen & Stratton, Orlando, Flo¬rida, page 182 (1984)).
Obwohl der Mechanismus der renalen Dysfunktion noch nicht voll¬ ständig aufgeklärt ist, konnte gezeigt werden, daß die renale Synthese von Thromboxan während des Fortschreitens von immun- und nicht immunvermittelten Modellen renaler Schädigung auftritt (Lianos et al . , J. Clin. Invest. 72: 1439-1448 (1983); Okegawa et al . , J. Clin. Invest. 71: 81-90 (1983)). Thromboxan ist ein Prostanoid und damit Metabolit der Arachidonsäure aus dem Cy- clooxigenasezyklus. Die anderen Prostanoide sind Prostaglandine und Prostacycline. Prostanoide sind sehr wirksame Mediatoren, die während immunologisch erzeugter Entzündungsprozesse entste¬ hen. Sie können grundlegend die renale Hämodynamik ändern (Mor- ley; in: Lymphokines, Herausgeber Pic, Academic Press, New York, 4: 377-391 (1981)).Although the mechanism of renal dysfunction has not yet been fully elucidated, it has been shown that renal synthesis of thromboxane occurs as immune-mediated and non-immune-mediated models of renal damage progress (Lianos et al., J. Clin. Invest. 72 : 1439-1448 (1983); Okegawa et al., J. Clin. Invest. 71: 81-90 (1983)). Thromboxan is a prostanoid and therefore a metabolite of arachidonic acid from the cyclooxygenase cycle. The other prostanoids are prostaglandins and prostacyclins. Prostanoids are very effective mediators that arise during immunologically generated inflammatory processes. They can fundamentally change renal hemodynamics (Morley; in: Lymphokines, publisher Pic, Academic Press, New York, 4: 377-391 (1981)).
EP-A-20 305 400 beschreibt die Zusammenhänge zwischen gestörter Prostanoidsynthese und Nephrotoxizität. Danach geht die Verab¬ reichung von Cyclosporin mit einer erhöhten Synthese von Throm¬ boxan B2, einem Mediator von Entzündungen, einher. Cyclosporin soll dementsprechend ebenfalls die Bildung von Prostaglandinen der E-Serie, ebenfalls Entzündungsmediatoren, fördern. Die Ab¬ stoßung menschlicher Nierentransplantate konnte in Verbindung gebracht werden mit einem schnellen Anstieg von renal eliminier¬ tem Thromboxan B2.EP-A-20 305 400 describes the connections between impaired prostanoid synthesis and nephrotoxicity. Thereafter, the administration of cyclosporin is accompanied by an increased synthesis of thromboxane B2, a mediator of inflammation. Accordingly, cyclosporin should also promote the formation of prostaglandins of the E series, also inflammation mediators. The rejection of human kidney transplants has been associated with a rapid increase in renally eliminated thromboxane B2.
EP-A-0 305 400 beschreibt ferner den Einsatz von w3-ungesättig- ten Fettsäuren in Kombination mit Cyclosporin A zur Hemmung der Prostaglandin- bzw. Thromboxanbi ldung.EP-A-0 305 400 also describes the use of w3-unsaturated fatty acids in combination with cyclosporin A to inhibit prostaglandin or thromboxane formation.
Ein Nachteil einer längerfristigen w3-Fettsäuregabe liegt in der Ausbildung eines Vitamin E-Mangelzustandes. Mangelzustände sind z. B. Hämolyse und eine verkürzte Lebensdauer der Erythrozyten. Im Tierexperiment führt Vitamin-E-Mangel zu degenerativen Mus- kelveränderungen, Kreatinurie, erhöhter Hämolyse der Erythro- zyten und zur Beeinflussung bestimmter Hormone und Enzyme sowie des Protein- und Arachidonsäurestoffwechseis (Machlin, Vitamin E. ; in: Machlin, Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects, Seiten 99-145, Marcel Dekker, New York, 1984).A disadvantage of long-term w3 fatty acid administration is the development of a vitamin E deficiency. Deficiency states are e.g. B. hemolysis and a shortened lifespan of the erythrocytes. In animal experiments, vitamin E deficiency leads to degenerative muscle changes in the muscles, creatinuria, increased hemolysis of the erythrocytes and to influence certain hormones and enzymes as well as the protein and arachidonic acid metabolism (Machlin, Vitamin E.; in: Machlin, Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects, pages 99-145, Marcel Dekker, New York, 1984).
Ein weiterer Nachteil dieser Zusammensetzung mit w3-ungesättig- ten Fettsäuren (Fischölen) ist die offenbar geringe zu errei- chende Wirkstoff onzentration in diesem öl. So beschreibt EP-A-0 305 400 lediglich eine Konzentration mit 12,5 mg Cyclosporin A pro Gramm Fischöl. Bei einer üblichen täglichen Dosis von mehr als 300 mg Cyclosporin A bedeutet das eine Gesamteinnahmemenge von etwa 24 Gramm der Zubereitung, bei 1 g Cyclosporin A von 80 g Zubereitung. Dieses ist eine für Patienten unzumutbar hohe Öl- enge, die beispielsweise in Weichgelatinekapseln verkapselt zu einer täglichen Einnahme von 24 Kapseln mit 300 mg Cyclosporin A führen würde. Die parenterale Applikation per Infusion würde bei einer, optimistisch gerechnet, 10-proz. ölhaltigen Infusions¬ emulsion eine Menge von ca. 240 ml Emulsion mit 300 mg Cyclospo¬ rin A bedeuten, ein Volumen, das nur über längere Zeit infun¬ diert werden kann. Beide Aspekte stehen einer chronischen Anwen¬ dung, wie sie bei Transplantationspatienten notwendig ist, abso¬ lut entgegen.Another disadvantage of this composition with w3-unsaturated fatty acids (fish oils) is the apparently low active substance concentration in this oil that can be achieved. For example, EP-A-0 305 400 only describes a concentration with 12.5 mg cyclosporin A per gram of fish oil. With a usual daily dose of more than 300 mg cyclosporin A, this means a total intake of about 24 grams of the preparation, with 1 g cyclosporin A of 80 g preparation. This is an oil level that is unacceptably high for patients. Encapsulated in soft gelatin capsules, for example, would lead to the daily intake of 24 capsules containing 300 mg cyclosporin A. Parenteral application by infusion would be, with an optimistic calculation, 10 percent. oil-containing infusion emulsion means an amount of approximately 240 ml of emulsion with 300 mg of cyclosporin A, a volume which can only be infused over a longer period of time. Both aspects stand in the way of a chronic application, as is necessary in transplant patients.
Die Formulierungen entsprechend der DE-B-2 907 460 zeichnen sich zwar durch ein sehr hohes Lösungsvermögen für Cyclosporin A aus, haben jedoch den Nachteil, daß sie nur Pflanzenöle umfassen, die keinerlei Prostaglandin- oder Thromboxansynthese-hemmende Stoffe enthalten. Das heißt, daß durch diese Zubereitungen die Nephro¬ toxizität des Cyclosporin A nicht gehemmt wird. Die im Handel befindliche parenterale Lösung des Cyclosporin A (SandimmunR , Firma Sandoz) enthält in 1 ml Lösung 50 mg Cyclosporin A, 32,9 % Ethanol und 650 mg Cremeopher EL, ein ethoxyliertes, hydriertes Rizinusöl. Neben der Ethanolmenge von 2 g pro Anwendung, die eine Belastung für die Leber darstellt, ist nach Literaturbe¬ richten Cremeopher EL nephrotoxisch ähnlich wie Cyclosporin A selber (Thiel et al . , Clin. Nephrol . 25 (Suppl. 1), 540-542 (1986); Finn et al . , Renal Failure 11, 3-15 (1989)). So führt Cremeopher EL in der isolierten, perfundierten Rattenniere zu einer deutlichen renalen Vasokonstriktion mit reduziertem re- nalen Blutfluß und tubulärer Dysfunktion (Besarab et al . , Trans¬ plantation 44, 195-201 (1987); Luke et al . , Transplantation 43, 795-799 (1987)). Im weiteren verursacht Cremeopher EL anaphylak- tische Reaktionen bis zum Schock (Chapuis et al . , Engl . J. Med. 312, 1259 (1985), Leunissen et al . , Lancet 1, 637 (1986); Maga- lini et al . , Transplantation 42, 443-444 (1986)). Als Ursache der anaphylaktoiden Reaktion wurde Cremop er EL angesehen, da es zu Histaminliberation führt (Ennis et al . , Agents Action 12, 64- 80 (1982)). In einigen Therapiefällen mit der i. v. Lösung wurde die allergische Reaktion bei der ersten Anwendung am Menschen beobachtet (Friedman et al . , Am J. Med 78, 343-345 (1985); Maga- lini et al . , Transplantation 42, 443-444 (1986)). Nachteil der handelsüblichen parenteralen Zubereitung ist demnach der In¬ haltsstoff Cremopher EL. Eine Formulierung ohne diesen Hilfs¬ stoff ist anzustreben, um die obigen Nebenwirkungen zu vermeiden und die Arzneimittelsicherheit zu erhöhen.The formulations according to DE-B-2 907 460 are distinguished by a very high solubility for cyclosporin A, but have the disadvantage that they only comprise vegetable oils which do not contain any substances which inhibit prostaglandin or thromboxane synthesis. This means that the nephro-toxicity of cyclosporin A is not inhibited by these preparations. The commercially available parenteral solution of cyclosporin A (Sandimmun R , Sandoz) contains in 1 ml solution 50 mg cyclosporin A, 32.9% ethanol and 650 mg cremeopher EL, an ethoxylated, hydrogenated castor oil. In addition to the amount of ethanol of 2 g per application, which is a burden on the liver, according to literature reports Cremeopher EL is nephrotoxically similar to cyclosporin A itself (Thiel et al., Clin. Nephrol. 25 (Suppl. 1), 540-542 (1986); Finn et al., Renal Failure 11, 3-15 (1989)). Thus, Cremeopher EL leads to a clear renal vasoconstriction with reduced renal blood flow and tubular dysfunction in the isolated, perfused rat kidney (Besarab et al., Transplantation 44, 195-201 (1987); Luke et al., Transplantation 43, 795-799 (1987)). Furthermore, Cremeopher EL causes anaphylactic reactions up to shock (Chapuis et al., Engl. J. Med. 312, 1259 (1985), Leunissen et al., Lancet 1, 637 (1986); Magalini et al. , Transplantation 42, 443-444 (1986)). Cremop er EL was considered to be the cause of the anaphylactoid reaction since it leads to histamine liberation (Ennis et al., Agents Action 12, 64-80 (1982)). In some therapy cases with the iv solution, the allergic reaction was observed when it was first used in humans (Friedman et al., Am J. Med 78, 343-345 (1985); Magalini et al., Transplantation 42, 443-444 (1986)). The disadvantage of the commercially available parenteral preparation is accordingly the ingredient Cremopher EL. A formulation without this auxiliary is to be aimed at in order to avoid the above side effects and to increase drug safety.
Die günstigen immunsuppressiven Eigenschaften von Cyclosporin A werden bei der Behandlung der Psoriasis ausgenutzt. Aufgrund seines hohen Molekulargewichts und seiner sehr hohen Lipophilie ist jedoch Cyclosporin A nicht imstande, intakte Haut, speziell das Stratum Corneum, zu durchdringen. Aus diesem Grunde werden schwere Psoriasisfälle mit der oralen und parenteralen Cyclo- sporingabe behandelt. Nachteil dieser Anwendung sind die syste¬ mischen Nebenwirkungen auf den Kreislauf (Hypertonie) und die Nierenfunktion. Topische Zubereitungen zur Behandlung der Psora- sis, womit die systemischen Nebenwirkungen reduziert würden, benötigen Resorptionsförderer wie z. B. Propylenglycol und Azone (Duncan et al . , British Journal of Dermatology 123: 631-640 (1990)). Nun ist aber gerade von Azone bekannt, daß seine per- meationsfördernden Eigenschaften auf eine Störung oder sogar Zerstörung der Schutzfunktion des Stratum Corneum zurückzuführen sind. Propylenglycol führt zu einem Austrocknen der Haut. Beide Substanzen würden also eher der Abheilung der Psoriasis hinder¬ lich als förderlich sein. Aus diesem Grunde wäre eine topische Zubereitung mit einem therapeutisch ausreichenden Cyclosporin-A- Gehalt in Kombination mit den Heilungsprozeß fördernden Stoffen wünschenswert. Darüber hinaus sollte die Kombination die Per- meation des Cyclosporin A durch intakte Haut fördern.The beneficial immunosuppressive properties of cyclosporin A are used in the treatment of psoriasis. However, due to its high molecular weight and its very high lipophilicity, cyclosporin A is unable to penetrate intact skin, especially the stratum corneum. For this reason, severe psoriasis cases are treated with oral and parenteral cyclospore administration. The disadvantage of this application is the systemic side effects on the circulation (hypertension) and kidney function. Topical preparations for the treatment of psoriasis, which would reduce the systemic side effects, require absorption promoters such as. B. Propylene glycol and Azone (Duncan et al., British Journal of Dermatology 123: 631-640 (1990)). Now it is known from Azone that its permeation-promoting properties are due to a disturbance or even destruction of the protective function of the stratum corneum are. Propylene glycol dries out the skin. Both substances would therefore hinder the healing of psoriasis rather than promote it. For this reason, a topical preparation with a therapeutically sufficient cyclosporin A content in combination with substances that promote the healing process would be desirable. In addition, the combination should promote the permeation of cyclosporin A through intact skin.
3. Aufgabe der Erfindung3. Object of the invention
Aufgabe der vorliegenden Erfindung ist es nun, ein vorteilhaftes LösungsmittelSystem zu finden, das Cyclosporin A in ausreichen¬ der Menge löst, so daß es in der therapeutisch gebräuchlichen täglichen Dosierung oral eingenommen werden kann, die nephro- toxische Wirkung reduzieren kann, bei topischer Applikation sowohl die Hautpermeation fördern als auch den Heilungsprozeß bei der Behandlung der Psoriasis unterstützen kann und zudem eine parenterale Applikation mit guter Verträglichkeit gewähr¬ leistet.It is an object of the present invention to find an advantageous solvent system which dissolves cyclosporin A in sufficient quantity so that it can be taken orally in the daily dosage which is used therapeutically and which can reduce the nephro-toxic effect, both when applied topically promote skin permeation as well as support the healing process in the treatment of psoriasis and also ensure parenteral administration with good tolerability.
4. Beschreibung der Erfindung4. Description of the invention
Die der Erfindung zugrundeliegende Aufgabe wird nun durch eine pharmazeutische Zubereitung gelöst, die aus Cyclosporin A und α- Tocopherol oder eines seiner Derivate besteht oder sie enthält.The object on which the invention is based is now achieved by a pharmaceutical preparation which consists of or contains cyclosporin A and α-tocopherol or one of its derivatives.
Diese pharmazeutische Zubereitung kann durch α-Tocopherol- Succinat, α-Tocopherol-Acetat oder D-α-Tocopherolpolyethylengly- kol-1000-Succinat als α-Tocopherol-Derivat gekennzeichnet sein.This pharmaceutical preparation can be characterized by α-tocopherol succinate, α-tocopherol acetate or D-α-tocopherol polyethylene glycol 1000 succinate as α-tocopherol derivative.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an α-Tocopherol in Form eines α-Tocopherol-Konzentrats in Pflan¬ zenöl gekennzeichnet sein. Die pharmazeutische Zubereitung kann durch Vermischen von Cyclosporin A mit einem α-Tocopherol-Konzentrat in Pflanzenöl erhältlich sein.The pharmaceutical preparation can furthermore be characterized by a content of α-tocopherol in the form of an α-tocopherol concentrate in vegetable oil. The pharmaceutical preparation can be obtained by mixing cyclosporin A with an α-tocopherol concentrate in vegetable oil.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an α-Tocopherol oder an einem seiner Derivate von bis zu 900 % auf Basis von Cyclosporin A gekennzeichnet sein.The pharmaceutical preparation can further be characterized by a content of α-tocopherol or one of its derivatives of up to 900% based on cyclosporin A.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an Cyclosporin A > 10 % auf Basis der Zusammensetzung ge¬ kennzeichnet sein.The pharmaceutical preparation can also be characterized by a content of cyclosporin A> 10% based on the composition.
Die pharmazeutische Zubereitung kann ferner durch seinen Gehalt an Ethanol oder Isopropanol als Verarbeitungshilfsmittel insbe¬ sondere in Mengen bis 20 % gekennzeichnet sein.The pharmaceutical preparation can also be characterized by its ethanol or isopropanol content as processing aid, in particular in amounts of up to 20%.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an einem E ulgator gekennzeichnet sein.The pharmaceutical preparation can furthermore be characterized by a content of an emulsifier.
Die pharmazeutische Zubereitung kann ferner durch einen Gehalt an Verdickungsmittel gekennzeichnet sein.The pharmaceutical preparation can also be characterized by a thickener content.
Die pharmazeutische Zubereitung kann schließlich in Form eines Injektionskonzentrats für Parenteralia mit dafür üblichen phy¬ siologisch verträglichen Hilfsstoffen vorgesehen werden.Finally, the pharmaceutical preparation can be provided in the form of an injection concentrate for parenterals with customary physiologically compatible auxiliaries.
Erfindungsgemäß wurde also überraschend gefunden, daß α-Tocophe¬ rol, sowie seine chemischen Derivate wie α-Tocopherol-Succinat und D-α-Trocopherolpolyethylenglycol-1000-Succinat und α-Toco¬ pherol-Acetat, insbesondere aber hochkonzentrierte Konzentrate von D-α-Tocopherol in Pflanzenölen, ein ausgezeichnetes Lösungs¬ vermögen für Cyclosporin A aufweisen, gleichzeitig die Synthese von Prostanoiden wie Prostaglandinen und Thromboxanen hemmen, was zur Reduktion der Nephrotoxizität und zum Abklingen von Entzündungsreaktionen in der Haut ausgenützt werden kann und
als membranstabilisierendes Antioxydans und hemmt die Frei¬ setzung von Histamin und hydrolytischen Enzymen z. B. aus den Mastzellen und den Lysosomen durch Stabilisierung ihrer Membra¬ nen. Ebenfalls hemmt es die Synthese bestimmter Prostaglandine, desaktiviert Sauerstoffradikale und entgiftet entsprechende Fol¬ geprodukte (Sies, Bildung von Superoxidradikalen und Peroxiden; in: Superoxiddismutase - Biochemie und therapeutscher Einsatz; Herausgeber Puhl & Ries, Perimed Verlag, Erlangen, 1982). Zudem erhöht Vitamin E die Hautfeuchigkeit und wirkt quasi als Okklusionsmittel . Alle diese beschriebenen Eigenschaften sind bei der Behandlung der Psoriasis von Vorteil.as a membrane stabilizing antioxidant and inhibits the release of histamine and hydrolytic enzymes e.g. B. from the mast cells and the lysosomes by stabilizing their membranes. It also inhibits the synthesis of certain prostaglandins, deactivates oxygen radicals and detoxifies corresponding secondary products (sies, formation of superoxide radicals and peroxides; in: superoxide dismutase - biochemistry and therapeutic use; publisher Puhl & Ries, Perimed Verlag, Erlangen, 1982). In addition, vitamin E increases skin moisture and acts as an occlusion agent. All of these properties described are beneficial in treating psoriasis.
Cyclosporin A löst sich nun völlig unerwartet in einer so hohen Konzentration > 10 % in Vitamin E-Zubereitungen wie Vitamin E- Konzentraten (Copherol F 1300), so daß die Kombination als Lö¬ sung therapeutisch sinnvoll sowohl in Weichgelatinekapseln als auch in topischen Formulierungen einsetzbar ist. Die Formulie¬ rungen können dabei zur Unterstützung der Verarbeitbarkeit ge¬ ringe Mengen Alkohol wie Ethanol oder Isopropanol in Mengen bis 20 % der Gesamtformulierung als auch zur Förderung der Benetzung physiologisch verträgliche oberflächenaktive Stoffe enthalten, das heißt Emulgatoren. Sowohl oral als topisch verträgliche Emulgatoren sind beispielsweise Phosphol ipide wie Lecithine, Ly- solecithine, Ethoxylierungsprodukte von Fettsäuren und Fetten, Alkaliseifen, Sucroseester und andere, ohne darauf beschränkt zu sein. Des weiteren können die Formulierungen Verdickungsmittel wie kolloidale Kieselsäure oder Polyacrylsäure oder Polyacryl- säurederivate oder Cellulosederivate sowie Antioxydantien und Geschmackshilfsstoffe enthalten.Cyclosporin A now completely unexpectedly dissolves in such a high concentration> 10% in vitamin E preparations as vitamin E concentrates (Copherol F 1300), so that the combination as a solution can be used therapeutically in both soft gelatin capsules and in topical formulations is. To support the processability, the formulations can contain small amounts of alcohol such as ethanol or isopropanol in amounts of up to 20% of the total formulation and also to promote the wetting of physiologically compatible surface-active substances, that is to say emulsifiers. Both orally and topically compatible emulsifiers are, for example, phospholipids such as lecithins, lysolecithins, ethoxylation products of fatty acids and fats, alkali soaps, sucrose esters and others, without being limited thereto. Furthermore, the formulations can contain thickeners, such as colloidal silica or polyacrylic acid or polyacrylic acid derivatives or cellulose derivatives, and also antioxidants and flavor aids.
5. Beispiele5. Examples
Beispiel 1: Zusammensetzung für eine WeichgelatinekapselExample 1: Composition for a soft gelatin capsule
Cyclosporin A 100 mgCyclosporin A 100 mg
Tocopherol (Copherol F1300) 900 mg Beispiel 2: Zusammensetzung für eine WeichgelatinekapselTocopherol (Copherol F1300) 900 mg Example 2: Composition for a soft gelatin capsule
Cyclosporin A 100 mgCyclosporin A 100 mg
Ethanol 100 mgEthanol 100 mg
Sojalecithin 200 mgSoy Lecithin 200 mg
Tocopherol (Copherol F1300) 600 mgTocopherol (Copherol F1300) 600 mg
Beispiel 3: Zusammensetzung für eine WeichgelatinekapselExample 3: Composition for a soft gelatin capsule
Cyclosporin A 125 mgCyclosporin A 125 mg
Ethanol abs. 125 mgEthanol abs. 125 mg
D-α-Tocopherol 325 mgD-α-tocopherol 325 mg
D-α-Tocopherylethylenglycol- 425 mg -1000-SuccinatD-α-tocopherylethylene glycol 425 mg -1000 succinate
Beispiel 4: Topiεche ZubereitungExample 4: Topical preparation
Cyclosporin A 10 mgCyclosporin A 10 mg
Tocopherol (Copherol F1300) 90 mgTocopherol (Copherol F1300) 90 mg
Lecithin 100 mgLecithin 100 mg
Isopropanol 200 mgIsopropanol 200 mg
Polyacrylsäure 15 mgPolyacrylic acid 15 mg
Triethanolamin 5 mgTriethanolamine 5 mg
Wasser ad 1000 mgWater ad 1000 mg
Beispiel 5: InjektionskonzentratExample 5: Injection concentrate
Cyclosporin A 50 mgCyclosporin A 50 mg
Tocopherol (Copherol F1300) 100 mgTocopherol (Copherol F1300) 100 mg
Lecithin 200 mgLecithin 200 mg
Ethanol 100 mgEthanol 100 mg
Eutanol 500 mg Eutanol 500 mg
Claims
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10199039C DE10199039I2 (en) | 1993-10-22 | 1994-09-30 | PHARMACEUTICAL COMPOSITION WITH CYCLOSPORIN A, A VITAMIN DERIVATIVE AND AN EMULSIFIER |
| DE59409377T DE59409377D1 (en) | 1993-10-22 | 1994-09-30 | PHARMACEUTICAL COMPOSITION WITH CYCLOSPORIN A, A VITAMIN E DERIVATIVE AND AN EMULSIFIER |
| EP94928852A EP0724452B1 (en) | 1993-10-22 | 1994-09-30 | Pharmaceutical composition containing cyclosporine a, a vitamine e derivative and an emulsifier |
| JP51123795A JP3644543B2 (en) | 1993-10-22 | 1994-09-30 | Pharmaceutical composition containing cyclosporin A and α-tocopherol |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4336163 | 1993-10-22 | ||
| DEP4336163.3 | 1993-10-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995011039A1 true WO1995011039A1 (en) | 1995-04-27 |
Family
ID=6500831
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1994/003274 Ceased WO1995011039A1 (en) | 1993-10-22 | 1994-09-30 | PHARMACEUTICAL COMPOSITION CONTAINING CYCLOSPORINE A AND α-TOCOPHEROL |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0724452B1 (en) |
| JP (1) | JP3644543B2 (en) |
| DE (2) | DE10199039I2 (en) |
| ES (1) | ES2148345T3 (en) |
| WO (1) | WO1995011039A1 (en) |
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| WO1997022358A1 (en) * | 1995-12-15 | 1997-06-26 | Bernard Charles Sherman | Microemulsion preconcentrates comprising cyclosporins |
| US5798333A (en) * | 1996-09-17 | 1998-08-25 | Sherman; Bernard C. | Water-soluble concentrates containing cyclosporins |
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-
1994
- 1994-09-30 JP JP51123795A patent/JP3644543B2/en not_active Expired - Lifetime
- 1994-09-30 DE DE10199039C patent/DE10199039I2/en active Active
- 1994-09-30 WO PCT/EP1994/003274 patent/WO1995011039A1/en not_active Ceased
- 1994-09-30 ES ES94928852T patent/ES2148345T3/en not_active Expired - Lifetime
- 1994-09-30 DE DE59409377T patent/DE59409377D1/en not_active Expired - Lifetime
- 1994-09-30 EP EP94928852A patent/EP0724452B1/en not_active Expired - Lifetime
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Also Published As
| Publication number | Publication date |
|---|---|
| EP0724452B1 (en) | 2000-05-24 |
| DE10199039I1 (en) | 2001-11-22 |
| DE10199039I2 (en) | 2008-08-07 |
| JP3644543B2 (en) | 2005-04-27 |
| JPH09504012A (en) | 1997-04-22 |
| DE59409377D1 (en) | 2000-06-29 |
| EP0724452A1 (en) | 1996-08-07 |
| ES2148345T3 (en) | 2000-10-16 |
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